This is an R21 Exploratory/Development grant application for two years of funding to develop and to apply novel image analysis techniques to better understand the white matter (WM) architecture of cognitive dysfunctions. This application qualifies as an R21 because it is a high-risk/high payoff technology research, development and enhancement project for the in vivo, non-invasive investigation of WM structure and function, which will likely have a high level of impact on the field. Our long-term goal is to identify in vivo WM fiber tracts (WMFT) which are specifically associated with key cognitive functions, and to improve our understanding of the association between disruption of WMFT by focal white matter lesions and cognitive performance. Focal white matter lesions are common across a range of diseases and syndromes, and are associated with decreased motor skills and decreased cognitive performance. Conventional magnetic resonance imaging (MRI) is now a standard clinically accepted mechanism to assess and to monitor white matter lesion presence and activity in the brain. Currently, studies to assess clinical disability are predominantly based upon lesion burden, that is, the total number or total size of plaques in the brain, or change in lesion burden as indicated by new lesions. This is not surprising given the fact that the analysis of WM has been hampered by technological limitations of image acquisition and post-acquisition image analysis, but it ignores the underlying role of the connectivity of WM in assessing the impact of WM abnormalities. Recent advances in diffusion tensor magnetic resonance imaging (DT-MRI), have provided the image acquisition technology to enable the new in vivo assessment of the role of white matter architecture of the human brain upon cognitive dysfunctions, which we propose here. The primary objective of this two-year R21 grant application is to research, develop and apply new image analysis techniques to enable the identification of white matter fiber tract segments that are disrupted by focal white matter lesions, and to identify the essential patterns of white matter disruption that are most highly correlated with decreased cognitive performance. These results will significantly improve our understanding of the relation between the anatomical location of focal white matter abnormalities, the connectivity of the white matter and cognitive impairment.